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Verona F, Di Bella S, Schirano R, Manfredi C, Angeloro F, Bozzari G, Todaro M, Giannini G, Stassi G, Veschi V. Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction. Front Immunol 2025; 16:1529847. [PMID: 39981232 PMCID: PMC11839637 DOI: 10.3389/fimmu.2025.1529847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.
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Affiliation(s)
- Francesco Verona
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Sebastiano Di Bella
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Roberto Schirano
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Camilla Manfredi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Francesca Angeloro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Giulia Bozzari
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” (AOUP), Palermo, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
- Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Giorgio Stassi
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
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Yarahmadi A, Dorri Giv M, Hosseininejad R, Rezaie A, Mohammadi N, Afkhami H, Farokhi A. Mesenchymal stem cells and their extracellular vesicle therapy for neurological disorders: traumatic brain injury and beyond. Front Neurol 2025; 16:1472679. [PMID: 39974358 PMCID: PMC11835705 DOI: 10.3389/fneur.2025.1472679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/08/2025] [Indexed: 02/21/2025] Open
Abstract
Traumatic brain injury (TBI) is a complex condition involving mechanisms that lead to brain dysfunction and nerve damage, resulting in significant morbidity and mortality globally. Affecting ~50 million people annually, TBI's impact includes a high death rate, exceeding that of heart disease and cancer. Complications arising from TBI encompass concussion, cerebral hemorrhage, tumors, encephalitis, delayed apoptosis, and necrosis. Current treatment methods, such as pharmacotherapy with dihydropyridines, high-pressure oxygen therapy, behavioral therapy, and non-invasive brain stimulation, have shown limited efficacy. A comprehensive understanding of vascular components is essential for developing new treatments to improve blood vessel-related brain damage. Recently, mesenchymal stem cells (MSCs) have shown promising results in repairing and mitigating brain damage. Studies indicate that MSCs can promote neurogenesis and angiogenesis through various mechanisms, including releasing bioactive molecules and extracellular vesicles (EVs), which help reduce neuroinflammation. In research, the distinctive characteristics of MSCs have positioned them as highly desirable cell sources. Extensive investigations have been conducted on the regulatory properties of MSCs and their manipulation, tagging, and transportation techniques for brain-related applications. This review explores the progress and prospects of MSC therapy in TBI, focusing on mechanisms of action, therapeutic benefits, and the challenges and potential limitations of using MSCs in treating neurological disorders.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Masoumeh Dorri Giv
- Nuclear Medicine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Hosseininejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azin Rezaie
- Department of Microbiology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Narges Mohammadi
- Department of Molecular Cell Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Arastoo Farokhi
- Department of Anesthesiology, Kermanshah University of Medical Sciences, Imam Reza Hospital, Kermanshah, Iran
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Li D, Yang Y, Zheng G, Meng L, Shang L, Ren J, Wang L, Bao Y. The potential of cellular homing behavior in tumor immunotherapy: from basic discoveries to clinical applications of immune, mesenchymal stem, and cancer cell homing. Front Immunol 2024; 15:1495978. [PMID: 39726590 PMCID: PMC11669694 DOI: 10.3389/fimmu.2024.1495978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/28/2024] [Indexed: 12/28/2024] Open
Abstract
The efficacy of immunotherapy, a pivotal approach in the arsenal of cancer treatment strategies, is contingent on the capacity of effector cells to localize at the tumor site. The navigational capacity of these cells is intricately linked to the homing behaviors of specific cell types. Recent studies have focused on leveraging immune cells and mesenchymal stem cells (MSCs) homing for targeted tumor therapy and incorporating cancer cell homing properties into anti-tumor strategies. However, research and development of immunotherapy based on cancer cell homing remain in their preliminary stages. Enhancing the homing efficiency of effector cells is essential; therefore, understanding the underlying mechanisms and addressing immune resistance within the tumor microenvironment and challenges associated with in vivo therapeutic agent delivery are essential. This review firstly delineates the discovery and clinical translation of the three principal cell-homing behaviors. Secondly, we endeavor to conduct an in-depth analysis of existing research on the homing of immune and stem cells in cancer therapy, with the aim of identifying and understanding of the common applications, potential benefits, barriers, and critical success factors of cellular homing therapies. Finally, based on the understanding of the key factors of cellular homing therapies, we provide an overview and outlook on the enormous potential of harnessing cancer cells' self-homing to treat tumors. Although immunotherapy based on cell-homing behavior warrants further research, it remains a highly competitive treatment modality that can be combined with existing classic anti-cancer therapies. In general, combining the homing properties of cells to optimize their clinical effects is also one of the future research directions in the field of cell transplantation.
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Affiliation(s)
- Dongtao Li
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yixuan Yang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guangda Zheng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linghan Meng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lu Shang
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Juanxia Ren
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Lingyun Wang
- First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Yanju Bao
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Enciso N, Enciso-Benavides J, Sandoval J, Enciso J. In Situ Treatment of Refractory Perianal Fistulas in Dogs with Low-Dose Allogeneic Adipose-Derived Mesenchymal Stem Cells. Animals (Basel) 2024; 14:3300. [PMID: 39595352 PMCID: PMC11591124 DOI: 10.3390/ani14223300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/24/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Stem cell therapy in dogs has increased considerably in recent years; however, there are few publications on the treatment of perianal fistulas (PF) in this species. The aim of this open-label clinical trial was to demonstrate the efficacy and safety of a new protocol for the in situ administration of low-dose adipose-derived allogeneic stem cells (ASCs) for the treatment of refractory spontaneous perianal fistula. The methodology consisted of applying one to three doses of 5 × 106 cryopreserved allogeneic ASCs to each fistula. The study was performed in 14 dogs regardless of sex, breed, or age, with a clinical diagnosis of refractory PF. Cells diluted in phosphate-buffered saline were applied to five sites of the PF in an amount of 1 × 106 per application site. Efficacy was determined by the complete closure of the fistula, which was observed in 100% of the cases studied one month after therapy, with a subsequent follow-up of 12 to 48 months after therapy. Furthermore, safety was demonstrated by the absence of local or systemic adverse effects. In conclusion, the protocol used in this work demonstrates the efficacy without adverse effects of the in situ application of low doses of allogeneic ASCs, providing a simple, non-invasive, long-lasting and low-cost therapeutic option.
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Affiliation(s)
- Nathaly Enciso
- Grupo Medicina Regenerativa, Universidad Científica del Sur, Lima 150142, Peru
| | - Javier Enciso-Benavides
- Clínica Veterinaria Enciso, Lima 15039, Peru;
- School of Veterinary Medicine, Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru
| | - Juan Sandoval
- Facultad de Medicina Veterinaria, Universidad San Luis Gonzaga de Ica, Ica 11770, Peru
| | - Javier Enciso
- Grupo Medicina Regenerativa, Universidad Científica del Sur, Lima 150142, Peru
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Antoon R, Overdevest N, Saleh AH, Keating A. Mesenchymal stromal cells as cancer promoters. Oncogene 2024; 43:3545-3555. [PMID: 39414984 PMCID: PMC11602730 DOI: 10.1038/s41388-024-03183-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 09/12/2024] [Accepted: 09/26/2024] [Indexed: 10/18/2024]
Abstract
Mesenchymal stromal cells (MSCs) are important cellular constituents of tumor stroma that play an active role in tumor development. Complex interactions between MSCs and cancer promote tumor progression by creating a favorable milieu for tumor cell proliferation, angiogenesis, motility, invasion, and metastasis. The cellular heterogeneity, source of origin, diversity in isolation methods, culture techniques and model systems of MSCs, together with the different tumor subtypes, add to the complexity of MSC-tumor interactions. In this review, we discuss the mechanisms of MSC-mediated tumor promotion and evaluate cell-stromal interactions between cancer cells, MSCs, cells of the tumor microenvironment (TME), and the extracellular matrix (ECM). A more thorough understanding of tumor-MSC interactions is likely to lead to better cancer management.
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Affiliation(s)
| | | | - Amr H Saleh
- Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
- Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, Toronto, ON, Canada.
- University Health Network, Toronto, ON, Canada.
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Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther 2024; 9:274. [PMID: 39420203 PMCID: PMC11491057 DOI: 10.1038/s41392-024-01979-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/20/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.
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Affiliation(s)
- Bo Wu
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Youth League Committee, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bowen Li
- Department of Pancreatic and Gastrointestinal Surgery, Ningbo No. 2 Hospital, Ningbo, China
| | - Haoqi Wu
- Department of Gynaecology and Obstetrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Meixi Jiang
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
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Urrata V, Toia F, Cammarata E, Franza M, Montesano L, Cordova A, Di Stefano AB. Characterization of the Secretome from Spheroids of Adipose-Derived Stem Cells (SASCs) and Its Potential for Tissue Regeneration. Biomedicines 2024; 12:1842. [PMID: 39200306 PMCID: PMC11351933 DOI: 10.3390/biomedicines12081842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 09/02/2024] Open
Abstract
INTRODUCTION Spheroids are spherical aggregates of cells that mimic the three-dimensional (3D) architecture of tissues more closely than traditional two dimensional (2D) cultures. Spheroids of adipose stem cells (SASCs) show special features such as high multilineage differentiation potential and immunomodulatory activity. These properties have been attributed to their secreted factors, such as cytokines and growth factors. Moreover, a key role is played by the extracellular vesicles (EVs), which lead a heterogeneous cargo of proteins, mRNAs, and small RNAs that interfere with the pathways of the recipient cells. PURPOSE The aim of this work was to characterize the composition of the secretome and exosome from SASCs and evaluate their regenerative potential. MATERIALS AND METHODS SASCs were extracted from adipose samples of healthy individuals after signing informed consent. The exosomes were isolated and characterized by Dinamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Western blotting analyses. The expression of mRNAs and miRNAs were evaluated through real-time PCR. Lastly, a wound-healing assay was performed to investigate their regenerative potential on different cell cultures. RESULTS The SASCs' exosomes showed an up-regulation of NANOG and SOX2 mRNAs, typical of stemness maintenance, as well as miR126 and miR146a, related to angiogenic and osteogenic processes. Moreover, the exosomes showed a regenerative effect. CONCLUSIONS The SASCs' secretome carried paracrine signals involved in stemness maintenance, pro-angiogenic and pro-osteogenic differentiation, immune system regulation, and regeneration.
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Affiliation(s)
- Valentina Urrata
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
| | - Francesca Toia
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
- Plastic and Reconstructive Surgery Unit, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy
| | - Emanuele Cammarata
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
- Plastic and Reconstructive Surgery Unit, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy
| | - Mara Franza
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
- Plastic and Reconstructive Surgery Unit, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy
| | - Luigi Montesano
- Plastic and Reconstructive Surgery Unit, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy
| | - Adriana Cordova
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
- Plastic and Reconstructive Surgery Unit, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy
| | - Anna Barbara Di Stefano
- BIOPLAST-Laboratory of Biology and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy (E.C.); (M.F.); (A.C.); (A.B.D.S.)
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Faircloth TU, Temple S, Parr RN, Tucker AB, Rajan D, Hematti P, Kugathasan S, Chinnadurai R. Vascular endothelial growth factor secretion and immunosuppression are distinct potency mechanisms of human bone marrow mesenchymal stromal cells. Stem Cells 2024; 42:736-751. [PMID: 38826008 DOI: 10.1093/stmcls/sxae040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/23/2024] [Indexed: 06/04/2024]
Abstract
Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, the combination of inflammatory cytokines IFNγ and TNFα reduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγ mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.
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Affiliation(s)
- Tyler U Faircloth
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Sara Temple
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Rhett N Parr
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Anna B Tucker
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Devi Rajan
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Peiman Hematti
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
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Takai M, Mori S, Honoki K, Tsujiuchi T. Roles of lysophosphatidic acid (LPA) receptor-mediated signaling in cancer cell biology. J Bioenerg Biomembr 2024; 56:475-482. [PMID: 38886303 DOI: 10.1007/s10863-024-10028-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 06/03/2024] [Indexed: 06/20/2024]
Abstract
Lysophosphatidic acid (LPA) is a simple lipid which is endogenously synthesized from lysophosphatidylcholine (LPC) by autotaxin (ATX). LPA mediates a variety of cellular responses through the binding of G protein-coupled LPA receptors (LPA1 to LPA6). It is considered that LPA receptor-mediated signaling plays an important role in the pathogenesis of human malignancy. Genetic alterations and epigenetic changes of LPA receptors have been detected in some cancer cells as well as LPA per se. Moreover, LPA receptors contribute to the promotion of tumor progression, including cell proliferation, invasion, metastasis, tumorigenicity, and angiogenesis. In recent studies, the activation of LPA receptor-mediated signaling regulates chemoresistance and radiosensitivity in cancer cells. This review provides an updated overview on the roles of LPA receptor-mediated signaling in the regulation of cancer cell functions and its potential utility as a molecular target for novel therapies in clinical cancer approaches.
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Affiliation(s)
- Miwa Takai
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4- 1, Kowakae, Higashiosaka, 577-8502, Osaka, Japan
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan
| | - Kanya Honoki
- Department of Orthopedic Oncology & Reconstructive Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4- 1, Kowakae, Higashiosaka, 577-8502, Osaka, Japan.
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Tang J, Chen Y, Wang C, Xia Y, Yu T, Tang M, Meng K, Yin L, Yang Y, Shen L, Xing H, Mao X. The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics. MedComm (Beijing) 2024; 5:e663. [PMID: 39070181 PMCID: PMC11283587 DOI: 10.1002/mco2.663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/30/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.
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Affiliation(s)
- Jian Tang
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Yu Chen
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
- Medical Affairs, Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Chunhua Wang
- Department of Clinical LaboratoryXiangyang No. 1 People's HospitalHubei University of MedicineXiangyangHubei ProvinceChina
| | - Ying Xia
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Tingyu Yu
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Mengjun Tang
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Kun Meng
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Lijuan Yin
- State Key Laboratory of Food Nutrition and SafetyKey Laboratory of Industrial MicrobiologyMinistry of EducationTianjin Key Laboratory of Industry MicrobiologyNational and Local United Engineering Lab of Metabolic Control Fermentation TechnologyChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal ChemistryCollege of BiotechnologyTianjin University of Science & TechnologyTianjinChina
| | - Yang Yang
- Shenzhen Key Laboratory of Pathogen and ImmunityNational Clinical Research Center for Infectious DiseaseState Key Discipline of Infectious DiseaseShenzhen Third People's HospitalSecond Hospital Affiliated to Southern University of Science and TechnologyShenzhenChina
| | - Liang Shen
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Hui Xing
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
- Department of Obstetrics and GynecologyXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and SciencesXiangyangChina
| | - Xiaogang Mao
- Central LaboratoryXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
- Department of Obstetrics and GynecologyXiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and SciencesXiangyangChina
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11
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Oliveira-Lopes AF, Götze MM, Lopes-Neto BE, Guerreiro DD, Bustamante-Filho IC, Moura AA. Molecular and Pathobiology of Canine Mammary Tumour: Defining a Translational Model for Human Breast Cancer. Vet Comp Oncol 2024. [PMID: 39011576 DOI: 10.1111/vco.12996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024]
Abstract
Canine mammary tumours (CMT) have histological, clinicopathological and molecular resemblances to human breast cancer (HBC), positioning them as viable models for studying the human disease. CMT initiation and progression occur spontaneously in immune-competent animals, which challenge the suggested limitations of genetically modified mice, also enabling the evaluation of immunotherapies in canine patients. Dogs have shorter life expectancy compared to humans, and cancer advances more rapidly in this species. This makes it possible to perform studies about the clinical efficacy of new therapeutic modalities in a much shorter time than in human patients. The identification of biomarkers for tumour subtypes, progression and treatment response paves the way for the development of novel therapeutic and diagnostic approaches. This review addresses the similarities between CMT and HBC and the molecular signatures identified in CMT samples that have been explored to date. We proposed a detailed molecular exploration of the CMT stroma using state-of-the-art methods in transcriptomics and proteomics. Using CMT as an analog for HBC not only helps to understand the complexities of the disease, but also to advance comparative oncology to the next level to prove the claim of dogs as a valid translational model.
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Affiliation(s)
| | - Marcelo M Götze
- Graduate Studies Program in Biotechnology, University of Vale do Taquari-Univates, Lajeado, Brazil
| | | | - Denise D Guerreiro
- Department of Animal Science, Federal University of Ceará, Fortaleza, Brazil
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12
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Zhou Z, Li Y, Wu S, Liu T, Jiang J. Host-microbiota interactions in collagen-induced arthritis rats treated with human umbilical cord mesenchymal stem cell exosome and ginsenoside Rh2. Biomed Pharmacother 2024; 174:116515. [PMID: 38569276 DOI: 10.1016/j.biopha.2024.116515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 04/05/2024] Open
Abstract
Mesenchymal stem cell exosome (MSCs-exo) is a class of products secreted by mesenchymal stem cells (MSCs) that contain various biologically active substances. MSCs-exo is a promising alternative to MSCs due to their lower immunogenicity and lack of ethical constraints. Ginsenoside Rh2 (Rh2) is a hydrolyzed component of the primary active substance of ginsenosides. Rh2 has a variety of pharmacological functions, including anti-inflammatory, anti-tumor, and antioxidant. Studies have demonstrated that gut microbiota and metabolites are critical in developing rheumatoid arthritis (RA). In this study, we constructed a collagen-induced arthritis (CIA) model in rats. We used MSCs-exo combined with Rh2 to treat CIA rats. To observe the effect of MSCs-exo combined with Rh2 on joint inflammation, rat feces were collected for 16 rRNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the arthritis index score and joint swelling of CIA rats treated with MSCs-exo in combination with Rh2 were significantly lower than those of the model and MSCs-exo alone groups. MSCs-exo and Rh2 significantly ameliorated the disturbed gut microbiota in CIA rats. The regulation of Candidatus_Saccharibacteria and Clostridium_XlVb regulation may be the most critical. Rh2 enhanced the therapeutic effect of MSCs-exo compared with the MSCs-exo -alone group. Furthermore, significant changes in gut metabolites were observed in the CIA rat group, and these differentially altered metabolites may act as messengers for host-microbiota interactions. These differential metabolites were enriched into relevant critical metabolic pathways, revealing possible pathways for host-microbiota interactions.
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Affiliation(s)
- Zhongsheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shuhui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Te Liu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China; Yibin Jilin University Research Institute, Jilin University, Yibin, Sichuan, China.
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China.
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13
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Bastian JLD, Zeuschner P, Stöckle M, Junker K, Linxweiler J. Tumor promoting effect of spheroids in an orthotopic prostate cancer mouse model. Sci Rep 2024; 14:8835. [PMID: 38632341 PMCID: PMC11024136 DOI: 10.1038/s41598-024-59052-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
In this study, we aimed to establish a technique for intraprostatic implantation of prostate cancer (PCa) spheroids and to identify the impact of three-dimensional organization of PCa cells on tumor progression and metastasis in a representative in vivo model. 40,000 LNCaP cells were implanted into the prostate of immunodeficient SCID mice either as single cells (n = 8) or as preformed 3D spheroids (n = 8). For a follow up of 20 weeks, tumor growth was monitored by serum PSA and high-resolution 3D ultrasonography. Eventually, animals were sacrificed and autopsied. The organ dissects were analyzed for the presence of metastases by histology (H&E) and immunohistochemistry (AMACR, AR, Ki-67, CK5, CK8, E-Cadherin, Vimentin). Solid intraprostatic tumors developed in 50% of mice after spheroid implantation and in 50% of mice after implantation of a single cells. Primary tumors of LNCaP spheroids evolved earlier, exhibiting a shorter tumor doubling time whilst developing larger tumor volumes, which was reflected by a higher immunohistochemical expression of Ki-67 and AR, too. Spheroid tumors established lung and lymph node metastases in 75% of mice, in contrast to 50% of mice after single cell implantation. Our technique enables a variety of studies regarding the influence of the tumor microenvironment on PCa progression.
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Affiliation(s)
- Julius Lars Daniel Bastian
- Department of Urology and Pediatric Urology, Saarland University, Kirrbergerstr. 100 Gebäude 6, 66424, Homburg, Germany
| | - Philip Zeuschner
- Department of Urology and Pediatric Urology, Saarland University, Kirrbergerstr. 100 Gebäude 6, 66424, Homburg, Germany
| | - Michael Stöckle
- Department of Urology and Pediatric Urology, Saarland University, Kirrbergerstr. 100 Gebäude 6, 66424, Homburg, Germany
| | - Kerstin Junker
- Department of Urology and Pediatric Urology, Saarland University, Kirrbergerstr. 100 Gebäude 6, 66424, Homburg, Germany
| | - Johannes Linxweiler
- Department of Urology and Pediatric Urology, Saarland University, Kirrbergerstr. 100 Gebäude 6, 66424, Homburg, Germany.
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14
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Taheri M, Tehrani HA, Dehghani S, Rajabzadeh A, Alibolandi M, Zamani N, Arefian E, Ramezani M. Signaling crosstalk between mesenchymal stem cells and tumor cells: Implications for tumor suppression or progression. Cytokine Growth Factor Rev 2024; 76:30-47. [PMID: 38341337 DOI: 10.1016/j.cytogfr.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stem cells (MSCs) have been extensively used in various therapeutic applications over the last two decades, particularly in regenerative medicine and cancer treatment. MSCs have the ability to differentiate into mesodermal and non-mesodermal lineages, which makes them a popular choice in tissue engineering and regenerative medicine. Studies have shown that MSCs have inherent tumor-suppressive properties and can affect the behavior of multiple cells contributing to tumor development. Additionally, MSCs possess a tumor tropism property and have a hypoimmune nature. The intrinsic features of MSCs along with their potential to undergo genetic manipulation and be loaded with various anticancer therapeutics have motivated researchers to use them in different cancer therapy approaches without considering their complex dynamic biological aspects. However, despite their desirable features, several reports have shown that MSCs possess tumor-supportive properties. These contradictory results signify the sophisticated nature of MSCs and warn against the potential therapeutic applications of MSCs. Therefore, researchers should meticulously consider the biological properties of MSCs in preclinical and clinical studies to avoid any undesirable outcomes. This manuscript reviews preclinical studies on MSCs and cancer from the last two decades, discusses how MSC properties affect tumor progression and explains the mechanisms behind tumor suppressive and supportive functions. It also highlights critical cellular pathways that could be targeted in future studies to improve the safety and effectiveness of MSC-based therapies for cancer treatment. The insights obtained from this study will pave the way for further clinical research on MSCs and development of more effective cancer treatments.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Rajabzadeh
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nina Zamani
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Rodrigues DB, Moreira HR, Jarnalo M, Horta R, Marques AP, Reis RL, Pirraco RP. Generation of 3D melanoma models using an assembloid-based approach. Acta Biomater 2024; 178:93-110. [PMID: 38382833 DOI: 10.1016/j.actbio.2024.02.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 01/31/2024] [Accepted: 02/13/2024] [Indexed: 02/23/2024]
Abstract
While 3D tumor models have greatly evolved over the past years, there is still a strong requirement for more biosimilar models which are capable of recapitulating cellular crosstalk within the tumor microenvironment while equally displaying representative levels of tumor aggressiveness and invasion. Herein, we disclose an assembloid melanoma model based on the fusion of individual stromal multicellular spheroids (MCSs). In contrast to more traditional tumor models, we show that it is possible to develop self-organizing, heterotypic melanoma models where tumor cells present stem-cell like features like up-regulated pluripotency master regulators SOX2, POU5F1 and NANOG. Additionally, these assembloids display high levels of invasiveness while embedded in 3D matrices as evidenced by stromal cell promotion of melanoma cell invasion via metalloproteinase production. Furthermore, sensitivity to anticancer drug doxorubicin was demonstrated for the melanoma assembloid model. These findings suggest that melanoma assembloids may play a significant role in the field of 3D cancer models as they more closely mimic the tumor microenvironment when compared to more traditional MCSs, opening the doors to a better understanding of the role of tumor microenvironment in supporting tumor progression. STATEMENT OF SIGNIFICANCE: The development of complex 3D tumor models that better recapitulate the tumor microenvironment is crucial for both an improved comprehension of intercellular crosstalk and for more efficient drug screening. We have herein developed a self-organizing heterotypic assembloid-based melanoma model capable of closely mimicking the tumor microenvironment. Key features recapitulated were the preservation of cancer cell stemness, sensitivity to anti-cancer agents and tumor cell invasion promoted by stromal cells. The approach of pre-establishing distinct stromal domains for subsequent combination into more complex tumor constructs provides a route for developing superior tumor models with a higher degree of similarity to native cancer tissues.
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Affiliation(s)
- Daniel B Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal
| | - Helena R Moreira
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal
| | - Mariana Jarnalo
- Department of Plastic and Reconstructive Surgery, and Burn Unity, Centro Hospitalar de São João, Porto, Portugal; Faculty of Medicine - University of Porto, Portugal
| | - Ricardo Horta
- Department of Plastic and Reconstructive Surgery, and Burn Unity, Centro Hospitalar de São João, Porto, Portugal; Faculty of Medicine - University of Porto, Portugal
| | - Alexandra P Marques
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal
| | - Rogério P Pirraco
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal.
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16
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Zhang N, Shu L, Liu Z, Shi A, Zhao L, Huang S, Sheng G, Yan Z, Song Y, Huang F, Tang Y, Zhang Z. The role of extracellular vesicles in cholangiocarcinoma tumor microenvironment. Front Pharmacol 2024; 14:1336685. [PMID: 38269274 PMCID: PMC10805838 DOI: 10.3389/fphar.2023.1336685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 12/26/2023] [Indexed: 01/26/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor that originates from the biliary system. With restricted treatment options at hand, the challenging aspect of early CCA diagnosis leads to a bleak prognosis. Besides the intrinsic characteristics of tumor cells, the generation and progression of CCA are profoundly influenced by the tumor microenvironment, which engages in intricate interactions with cholangiocarcinoma cells. Of notable significance is the role of extracellular vesicles as key carriers in enabling communication between cancer cells and the tumor microenvironment. This review aims to provide a comprehensive overview of current research examining the interplay between extracellular vesicles and the tumor microenvironment in the context of CCA. Specifically, we will emphasize the significant contributions of extracellular vesicles in molding the CCA microenvironment and explore their potential applications in the diagnosis, prognosis assessment, and therapeutic strategies for this aggressive malignancy.
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Affiliation(s)
- Nuoqi Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Lizhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Department of General Surgery, Qilu Hospital, Shandong University, Qingdao, Shandong, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Liming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Guoli Sheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhangdi Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Song
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Fan Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yongchang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
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17
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Zhang S, Yahaya BH, Pan Y, Liu Y, Lin J. Menstrual blood-derived endometrial stem cell, a unique and promising alternative in the stem cell-based therapy for chemotherapy-induced premature ovarian insufficiency. Stem Cell Res Ther 2023; 14:327. [PMID: 37957675 PMCID: PMC10644549 DOI: 10.1186/s13287-023-03551-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
Chemotherapy can cause ovarian dysfunction and infertility since the ovary is extremely sensitive to chemotherapeutic drugs. Apart from the indispensable role of the ovary in the overall hormonal milieu, ovarian dysfunction also affects many other organ systems and functions including sexuality, bones, the cardiovascular system, and neurocognitive function. Although conventional hormone replacement therapy can partly relieve the adverse symptoms of premature ovarian insufficiency (POI), the treatment cannot fundamentally prevent deterioration of POI. Therefore, effective treatments to improve chemotherapy-induced POI are urgently needed, especially for patients desiring fertility preservation. Recently, mesenchymal stem cell (MSC)-based therapies have resulted in promising improvements in chemotherapy-induced ovary dysfunction by enhancing the anti-apoptotic capacity of ovarian cells, preventing ovarian follicular atresia, promoting angiogenesis and improving injured ovarian structure and the pregnancy rate. These improvements are mainly attributed to MSC-derived biological factors, functional RNAs, and even mitochondria, which are directly secreted or indirectly translocated with extracellular vesicles (microvesicles and exosomes) to repair ovarian dysfunction. Additionally, as a novel source of MSCs, menstrual blood-derived endometrial stem cells (MenSCs) have exhibited promising therapeutic effects in various diseases due to their comprehensive advantages, such as periodic and non-invasive sample collection, abundant sources, regular donation and autologous transplantation. Therefore, this review summarizes the efficacy of MSCs transplantation in improving chemotherapy-induced POI and analyzes the underlying mechanism, and further discusses the benefit and existing challenges in promoting the clinical application of MenSCs in chemotherapy-induced POI.
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Affiliation(s)
- Shenghui Zhang
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Penang, Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Penang, Malaysia
| | - Ying Pan
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, , China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China.
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18
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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19
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Safari F, Dadvar F. In vitro evaluation of autophagy and cell death induction in Panc1 pancreatic cancer by secretome of hAMSCs through downregulation of p-AKT/p-mTOR and upregulation of p-AMPK/ULK1 signal transduction pathways. Tissue Cell 2023; 84:102160. [PMID: 37482027 DOI: 10.1016/j.tice.2023.102160] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/21/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023]
Abstract
One of the main causes of cancer mortality in the world is pancreatic cancer. Therapies based on stem cells are currently thought to be a hopeful option in the treatment of cancer. Herein, we intend to evaluate the antitumor effects of secretome of human amniotic mesenchymal stromal cells (hAMSCs) on autophagy and cell death induction in Panc1 pancreatic cancer cells. We adopted a co-culture system using Transwell 6-well plates and after 72 h, hAMSCs-treated Panc1 cancer cells were analyzed using quantitative real time PCR (qRT-PCR), flow cytometry, western blot, MTT assay, and DAPI staining. Based on our results, the microtubule-associated protein 1 light chain 3 (LC3) conversion from LC3-I to LC3-II and the upregulation of autophagy-related proteins expression including Beclin1, Atg7, and Atg12 were detected in hAMSCs-treated Panc1 cells. Furthermore, the level of phosphorylated proteins such as Unc-51-like kinase 1 (ULK1), AMP activated protein kinase (AMPK), AKT, and mTOR changed. Apoptotic cell death was also induced via the elevation of Bax and Caspase 3 expression and inhibition of Bcl-2. Our findings showed that secretome of hAMSCs induces autophagy and cell death in Panc1 cancer cells. However, more experiments will be needed to identify more details about the associated mechanisms.
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Affiliation(s)
- Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
| | - Faezeh Dadvar
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
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20
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Bakhtiyari M, Liaghat M, Aziziyan F, Shapourian H, Yahyazadeh S, Alipour M, Shahveh S, Maleki-Sheikhabadi F, Halimi H, Forghaniesfidvajani R, Zalpoor H, Nabi-Afjadi M, Pornour M. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways. Cell Commun Signal 2023; 21:252. [PMID: 37735675 PMCID: PMC10512514 DOI: 10.1186/s12964-023-01282-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/17/2023] [Indexed: 09/23/2023] Open
Abstract
Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.
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Affiliation(s)
- Maryam Bakhtiyari
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahsa Liaghat
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Fatemeh Aziziyan
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hooriyeh Shapourian
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maedeh Alipour
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Shaghayegh Shahveh
- American Association of Naturopath Physician (AANP), Washington, DC, USA
| | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Halimi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Razieh Forghaniesfidvajani
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA.
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21
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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22
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Lv S, Liu Y, Xie C, Xue C, Du S, Yao J. Emerging role of interactions between tumor angiogenesis and cancer stem cells. J Control Release 2023; 360:468-481. [PMID: 37391031 DOI: 10.1016/j.jconrel.2023.06.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/16/2023] [Accepted: 06/27/2023] [Indexed: 07/02/2023]
Abstract
Tumor angiogenesis and cancer stem cells (CSCs) are two major hallmarks of solid tumors. They have long received attention for their critical roles in tumor progression, metastasis and recurrence. Meanwhile, plenty of evidence indicates the close association between CSCs and tumor vasculature. CSCs are proven to promote tumor angiogenesis, and the highly vascularized tumor microenvironment further maintains CSCs growth in return, thereby forming a hard-breaking vicious circle to promote tumor development. Hence, though monotherapy targeting tumor vasculature or CSCs has been extensively studied over the past decades, the poor prognosis has been limiting the clinical application. This review summarizes the crosstalk between tumor vasculature and CSCs with emphasis on small-molecule compounds and the associated biological signaling pathways. We also highlight the importance of linking tumor vessels to CSCs to disrupt the CSCs-angiogenesis vicious circle. More precise treatment regimens targeting tumor vasculature and CSCs are expected to benefit future tumor treatment development.
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Affiliation(s)
- Shuai Lv
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Yufei Liu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Changheng Xie
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Chenyang Xue
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Shi Du
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
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23
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Moradi-Gharibvand N, Hashemibeni B. The Effect of Stem Cells and Vascular Endothelial Growth Factor on Cancer Angiogenesis. Adv Biomed Res 2023; 12:124. [PMID: 37434939 PMCID: PMC10331557 DOI: 10.4103/abr.abr_378_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 04/17/2022] [Accepted: 04/24/2022] [Indexed: 07/13/2023] Open
Abstract
The formation of new vessels from pre-existing vessels is known as angiogenesis. The process is controlled by stimuli and inhibitors. Angiogenesis starts as a result of the unbalance of these factors, where balance has a tendency toward the stimulus. One of the most important factors promoting angiogenesis is the vascular endothelial growth factor (VEGF). In addition to being involved in vascular regeneration in normal tissues, VEGF also takes part in tumor tissue angiogenesis. These factors affect endothelial cells (ECs) directly as well as differentiate tumor cells from endothelial cells and play an active role in tumor tissue angiogenesis. Angiogenesis partakes in the growth and proliferation of tumor tissue. Because anti-angiogenic treatment is favorable in existing cancer therapies, the potential benefits should be considered. One of these new therapies is cell therapy using mesenchymal stem cells (MSCs). Research on MSCs remains controversial because much of the earlier research on MSCs has shown their effectiveness, but more recent research has identified harmful effects of these cells. This article reviews the role of stem cells and their secretions in the angiogenesis of tumor tissues.
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Affiliation(s)
- Nahid Moradi-Gharibvand
- Abadan University of Medical Sciences, Abadan, Iran
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Batool Hashemibeni
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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24
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Akad F, Mocanu V, Peiu SN, Scripcariu V, Filip B, Timofte D, Zugun-Eloae F, Cuciureanu M, Hancianu M, Oboroceanu T, Condur L, Popa RF. Mesenchymal Stem Cell-Derived Exosomes Modulate Angiogenesis in Gastric Cancer. Biomedicines 2023; 11:biomedicines11041031. [PMID: 37189649 DOI: 10.3390/biomedicines11041031] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant changes in chronic gastritis. The successful use of transplanted mesenchymal stem cells (MSCs) for gastric ulcer healing has raised interest in studying their effects on tumor neovascularization and in potential antiangiogenic therapies that could use mesenchymal stem cell secretion into extracellular vesicles—such as exosomes—in GC cells. The use of MSCs isolated from bone marrow in order to achieve angiogenic modulation in the tumor microenvironment could exploit the inherent migration of MSCs into GC tissues. Bone marrow-derived MSCs naturally present in the stomach have been reported to carry a malignancy risk, but their effect in GC is still being researched. The pro- and antiangiogenic effects of MSCs derived from various sources complement their role in immune regulation and tissue regeneration and provide further understanding into the heterogeneous biology of GC, the aberrant morphology of tumor vasculature and the mechanisms of resistance to antiangiogenic drugs.
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25
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Sheykhbahaei N, Bayramzadeh F, Koopaie M. Transdifferentiation of periodontal ligament stem cells into acinar cells using an indirect co-culture system. Cell Tissue Bank 2023; 24:241-251. [PMID: 35982342 DOI: 10.1007/s10561-022-10029-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/13/2022] [Indexed: 11/29/2022]
Abstract
Serous Acinar Cells (ACs) are mature and functional secretory epithelial cells that develop and complete through other stem cells at the end of the ductal system. So, the regeneration of the salivary gland damaged by radiation does not occur without cell therapy. Todays, an accessible tissue like the Periodontal Ligament (PDL) of the tooth was considered to easily extract the Mesenchymal Stem Cells (MSCs). In-vitro differentiation of stem cells before transplantation to damaged tissue reduces the risk of tumorigenesis. This study was conducted to evaluate the feasibility of differentiation of PDLSCs into salivary acinar cells by a co-culture system. PDLSCs were isolated from adult human PDL tissue and co-cultured with rat parotid ACs using an indirect co-culture system. The transdifferentiation of PDLSCs was evaluated by PCR of Aquaporin 5 (AQP5) and Carbonic anhydrase 6 (CA6) genes, then quantitative real-time PCR was used to measure the gene expression levels. The data were analyzed by ANOVA. Specific bond with the correct size on 6% acrylamide gel and TBE5X buffer showed the expression of AQP5 and CA6 in PDLSCs co-cultured with acinar cells. RT-PCR revealed co-cultured PDLSCs with or without KGF (Keratinocyte Growth Factor) showed significantly increased expression of AQP5 genes in compared to the initial PDLSCs. Expression of AQP5 and CA6, indicating successful transdifferentiation of PDLSCs into ACs, in co-culture system for 3 weeks.
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Affiliation(s)
- Nafiseh Sheykhbahaei
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran
| | | | - Maryam Koopaie
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran.
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26
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Xie L, Zhang C, Liu M, Huang J, Jin X, Zhu C, Lv M, Yang N, Chen S, Shao M, Du X, Feng G. Nucleus-Targeting Manganese Dioxide Nanoparticles Coated with the Human Umbilical Cord Mesenchymal Stem Cell Membrane for Cancer Cell Therapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:10541-10553. [PMID: 36787533 PMCID: PMC9982816 DOI: 10.1021/acsami.3c01176] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 02/03/2023] [Indexed: 05/29/2023]
Abstract
Recently, development of drug delivery systems for accurate delivery of antitumor drugs to tumor sites to improve their antitumor efficacy has attracted great interest in the area of cancer immunotherapy. In this report, an intelligent biodegradable hollow manganese dioxide (HMnO2) nanoparticle (NP) with a human umbilical cord mesenchymal stem cell (hUC-MSC) membrane coating was designed to exert efficient chemo-immunotherapy for cancer treatment. A TAT peptide-modified membrane structure was constructed for nuclear targeting. Our findings showed that this new nanoreactor inherited the active targeting capability of MSCs and exhibited tumoritropic accumulation significantly at the cancerous parts. Compared with other formulations, intravenous injection of the NPs markedly inhibited tumor growth, relapse, and metastasis. Moreover, we found that the NPs effectively boosted dendritic cell maturation and recruited effector T cells into tumors. Overall, this work demonstrates the great potential of applying MSC membrane-coated manganese dioxide NPs as nucleus-targeting nanocarriers in cancer chemo-immunotherapy.
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Affiliation(s)
- Lixu Xie
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
- Department
of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Changwen Zhang
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Miao Liu
- Department
of Pediatrics, Qingyun County People’s
Hospital, Dezhou 253700, China
| | - Jianling Huang
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Xiao Jin
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Changjun Zhu
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Minjie Lv
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Ning Yang
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Sixi Chen
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Mingyue Shao
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Xingran Du
- Department
of Infectious Disease, The Second Affiliated
Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
| | - Ganzhu Feng
- Department
of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211000, China
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27
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The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies. Stem Cells Int 2023; 2023:7059289. [PMID: 36824409 PMCID: PMC9943627 DOI: 10.1155/2023/7059289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 01/17/2023] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.
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28
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Zhang Y, Liang F, Zhang D, Qi S, Liu Y. Metabolites as extracellular vesicle cargo in health, cancer, pleural effusion, and cardiovascular diseases: An emerging field of study to diagnostic and therapeutic purposes. Biomed Pharmacother 2023; 157:114046. [PMID: 36469967 DOI: 10.1016/j.biopha.2022.114046] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/19/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Extracellular vesicles (EVs) are highly diverse nanoscale membrane-bound structures released from different cell types into the extracellular environment. They play essential functions in cell signaling by transporting their cargo, such as proteins, RNA, DNA, lipids, metabolites, and small molecules, to recipient cells. It has recently been shown that EVs might modulate carcinogenesis by delivering cargo to recipient cells. Furthermore, recent discoveries revealed that changes in plasma-derived EV levels and cargo in subjects with metabolic diseases were documented by many researchers, suggesting that EVs might be a promising source of disease biomarkers. One of the cargos of EVs that has recently attracted the most attention is metabolites. The metabolome of these vesicles introduces a plethora of disease indicators; hence, examining the metabolomics of EVs detected in human biofluids would be an effective approach. On the other hand, metabolites have various roles in biological systems, including the production of energies, synthesizing macromolecules, and serving as signaling molecules and hormones. Metabolome rewiring in cancer and stromal cells is a characteristic of malignancy, but the current understanding of how this affects the metabolite composition and activity of tumor-derived EVs remains in its infancy. Since new findings and studies in the field of exosome biology and metabolism are constantly being published, it is likely that diagnostic and treatment techniques, including the use of exosome metabolites, will be launched in the coming years. Recent years have seen increased interest in the EV metabolome as a possible source for biomarker development. However, our understanding of the role of these molecules in health and disease is still immature. In this work, we have provided the latest findings regarding the role of metabolites as EV cargoes in the pathophysiology of diseases, including cancer, pleural effusion (PE), and cardiovascular disease (CVD). We also discussed the significance of metabolites as EV cargoes of microbiota and their role in host-microbe interaction. In addition, the latest findings on metabolites in the form of EV cargoes as biomarkers for disease diagnosis and treatment are presented in this study.
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Affiliation(s)
- Yan Zhang
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, People's Republic of China
| | - Feng Liang
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, People's Republic of China
| | - DuoDuo Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Shuang Qi
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, People's Republic of China.
| | - Yan Liu
- Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, People's Republic of China.
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29
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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30
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Hemigraphis alternata Leaf Extract Incorporated Agar/Pectin-Based Bio-Engineered Wound Dressing Materials for Effective Skin Cancer Wound Care Therapy. Polymers (Basel) 2022; 15:polym15010115. [PMID: 36616465 PMCID: PMC9823803 DOI: 10.3390/polym15010115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/08/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
The rapidly expanding area of regenerative medicine may soon enter a new phase owing to developments in biomaterials and their application in generating new tissues. Chemicals and synthetic drugs are currently the subject of heated debate due to their effects on human health and the environment. Therefore, scientists seek out new products and procedures that are harmless to both the environment and human health concerns. Bio-based materials provide excellent functional qualities with a variety of applications. This study resulted in the development of a film with antimicrobial, hydrophilic, and anti-cancer properties, which is most beneficial in the medical sectors. In this study, we developed a blended biodegradable film containing agar and pectin (AP), with excellent surface functional properties framed through a casting technique. Additionally, the property can be changed by the addition of extract of hemigraphis alternata (HA) extract. The incorporation of extract in AP (APH) can be used for anti-cancer wound care therapy. The fabricated film is biodegradable, biocompatible, and non-toxic. This material is entirely based on a green methodology, and it was prepared in a concise manner without the use of any hazardous solvents. Based on the overall nature of biopolymer, the prepared material is a promising alternative to our society.
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Xu M, Zhang T, Xia R, Wei Y, Wei X. Targeting the tumor stroma for cancer therapy. Mol Cancer 2022; 21:208. [PMID: 36324128 PMCID: PMC9628074 DOI: 10.1186/s12943-022-01670-1] [Citation(s) in RCA: 138] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/13/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
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Affiliation(s)
- Maosen Xu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Tao Zhang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Ruolan Xia
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China.
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Nachmias B, Zimran E, Avni B. Mesenchymal stroma/stem cells: Haematologists' friend or foe? Br J Haematol 2022; 199:175-189. [PMID: 35667616 PMCID: PMC9796884 DOI: 10.1111/bjh.18292] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 01/07/2023]
Abstract
Mesenchymal stromal cells (MSCs) are non-haematopoietic cells found in fetal and adult organs, that play important roles in tissue repair, inflammation and immune modulation. MSCs residing in the bone marrow interact closely with haematopoietic cells and comprise an important component of the microenvironment supporting haematopoiesis, in both health and disease states. Since their identification in 1970, basic scientific and preclinical research efforts have shed light on the role of MSCs in the regulation of haematopoiesis and evoked interest in their clinical application in haematopoietic stem cell transplantation (HSCT) and malignant haematology. Over the last two decades, these research efforts have led to numerous clinical trials, which have established the safety of MSC therapy; however, the optimal mode of administration and the benefit remain inconclusive. In this paper, we will review the clinical experience with use of MSCs in HSCT for enhancement of engraftment, prevention and treatment of graft-versus-host disease and haemorrhagic cystitis. Then, we will discuss the contradictory evidence regarding tumour-promoting versus tumour-suppressing effects of MSCs in haematological malignancies, which may have relevance for future clinical applications.
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Affiliation(s)
- Boaz Nachmias
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Eran Zimran
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Batia Avni
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
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Breast Tumor Cell-Stimulated Bone Marrow-Derived Mesenchymal Stem Cells Promote the Sprouting Capacity of Endothelial Cells by Promoting VEGF Expression, Mediated in Part through HIF-1α Increase. Cancers (Basel) 2022; 14:cancers14194711. [PMID: 36230633 PMCID: PMC9562024 DOI: 10.3390/cancers14194711] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/22/2022] [Accepted: 09/25/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary ROS and JAK/Stat3 cooperatively upregulate the expression of HIF-1α in bone marrow-derived mesenchymal stem cells under normoxic conditions in response to breast tumor cells. The upregulation of HIF-1α contributes in part to the increase in VEGF expression in the bone marrow-derived mesenchymal stem cells. Bone marrow-derived mesenchymal stem cells improve the angiogenic sprouting capacity of mature endothelial cells in a VEGF-dependent manner. Abstract Breast tumor cells recruit bone marrow-derived mesenchymal stem cells (BM-MSCs) and alter their cellular characteristics to establish a tumor microenvironment. BM-MSCs enhance tumor angiogenesis through various mechanisms. We investigated the mechanisms by which BM-MSCs promote angiogenesis in response to breast tumor. Conditioned media from MDA-MB-231 (MDA CM) and MCF7 (MCF7 CM) breast tumor cells were used to mimic breast tumor conditions. An in vitro spheroid sprouting assay using human umbilical vein endothelial cells (HUVECs) was conducted to assess the angiogenesis-stimulating potential of BM-MSCs in response to breast tumors. The ROS inhibitor N-acetylcysteine (NAC) and JAK inhibitor ruxolitinib attenuated increased HIF-1α in BM-MSCs in response to MDA CM and MCF7 CM. HIF-1α knockdown or HIF-1β only partially downregulated VEGF expression and, therefore, the sprouting capacity of HUVECs in response to conditioned media from BM-MSCs treated with MDA CM or MCF7 CM. Inactivation of the VEGF receptor using sorafenib completely inhibited the HUVECs’ sprouting. Our results suggest that increased HIF-1α expression under normoxia in BM-MSCs in response to breast tumor cells is mediated by ROS and JAK/Stat3, and that both HIF-1α-dependent and -independent mechanisms increase VEGF expression in BM-MSCs to promote the angiogenic sprouting capacity of endothelial cells in a VEGF-dependent manner.
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Urrata V, Trapani M, Franza M, Moschella F, Di Stefano AB, Toia F. Analysis of MSCs' secretome and EVs cargo: Evaluation of functions and applications. Life Sci 2022; 308:120990. [PMID: 36155182 DOI: 10.1016/j.lfs.2022.120990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/12/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022]
Affiliation(s)
- Valentina Urrata
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Marco Trapani
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy
| | - Mara Franza
- Plastic and Reconstructive Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy; Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Francesco Moschella
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Anna Barbara Di Stefano
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Francesca Toia
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy; Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
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Ramuta TŽ, Kreft ME. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers (Basel) 2022; 14:cancers14153761. [PMID: 35954425 PMCID: PMC9367361 DOI: 10.3390/cancers14153761] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Tumours consist of different cell types and an extracellular matrix, all of which together form a complex microenvironment. The tumour microenvironment plays a critical role in various aspects of tumour development and progression. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that have a tri-lineage differentiation capacity and are one of the key stromal cells in the tumour microenvironment. Following the interaction with cancer cells, they are transformed from naïve MSCs to tumour-associated MSCs, which substantially affect tumour growth and progression as well as the development of chemoresistance in cancer cells. The aim of this review article is to provide an overview of studies that have investigated how MSCs affect the susceptibility of cancer cells to chemotherapeutics. Their results show that MSCs protect cancer cells from chemotherapeutics by influencing several signalling pathways. This knowledge is crucial for the development of new treatment approaches that will lead to improved treatment outcomes. Abstract The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.
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Antoon R, Wang XH, Saleh AH, Warrington J, Hedley DW, Keating A. Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell-derived IL-6 is reversed predominantly by IL-6 blockade. Cytotherapy 2022; 24:699-710. [PMID: 35473998 DOI: 10.1016/j.jcyt.2021.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022]
Abstract
Pancreatic cancer is a highly lethal cancer characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease, and interactions between cancer and stromal cells are critical for pancreatic cancer development and progression. Mesenchymal stromal cells [MSCs] exhibit preferential tropism to primary and metastatic tumor sites and may either suppress or support tumor growth. Although MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSCs significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSCs create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis, including interleukin (IL)-6, IL-8, vascular endothelial growth factor and activation of STAT3 signaling in tumor cells. IL-6 released by MSCs was largely responsible for the pro-tumorigenic effects of MSCs. Knockdown of IL-6 expression in MSCs by small interfering RNA (siRNA) abolished the MSC growth-promoting effect in vitro, reducing tumor cell proliferation and clonogenic potential. In addition, in a heterotopic nude mouse model of human pancreatic tumor xenografts, blockade of IL-6 with the anti-IL-6 receptor antibody, tocilizumab, or of its downstream effector STAT3 with the small molecule STAT3 inhibitor S3I-201, abrogated MSC-mediated tumor promotion and delayed tumor formation significantly. Our data demonstrate that MSCs promote pancreatic cancer growth, with IL-6 produced by MSCs playing a pivotal role.
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Affiliation(s)
- Roula Antoon
- Krembil Research Institute, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | | | - Amr H Saleh
- Krembil Research Institute, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - David W Hedley
- Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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Yang T, Tang S, Peng S, Ding G. The Effects of Mesenchymal Stem Cells on Oral Cancer and Possible Therapy Regime. Front Genet 2022; 13:949770. [PMID: 35846142 PMCID: PMC9280436 DOI: 10.3389/fgene.2022.949770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are characterized by self-renewal, rapid proliferation, multipotent differentiation, and low immunogenicity. In addition, the tropism of MSCs towards injured tissues and tumor lesions makes them attractive candidates as cell carriers for therapeutic agent delivery and genetic material transfer. The interaction between tumor cells and MSCs in the tumor microenvironment plays an important role in tumor progression. Oral cancer is one of the most common malignant diseases in the head and neck. Although considerable improvements in the treatment of oral cancer were achieved, more effective and safer novel agents and treatments are still needed, and deeper studies on the etiology, pathology, and treatment of the oral cancer are desirable. In the past decades, many studies have reported the beneficial effects of MSCs-based therapies in the treatment of various diseases, including oral cancers. Meanwhile, other studies demonstrated that MSCs may enhance the growth and metastasis of oral cancer. In this paper, we reviewed the research progress of the effects of MSCs on oral cancers, the underlying mechanisms, and their potential applications in the treatment of oral cancers.
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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Gilazieva Z, Ponomarev A, Rizvanov A, Solovyeva V. The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis. BIOLOGY 2022; 11:biology11060813. [PMID: 35741334 PMCID: PMC9220333 DOI: 10.3390/biology11060813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described. Abstract Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.
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Frisbie L, Buckanovich RJ, Coffman L. Carcinoma Associated Mesenchymal Stem/Stromal Cells - Architects of the Pro-tumorigenic tumor microenvironment. Stem Cells 2022; 40:705-715. [PMID: 35583414 PMCID: PMC9406606 DOI: 10.1093/stmcls/sxac036] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022]
Abstract
The interaction between tumor cells and non-malignant hosts cells within the tumor microenvironment (TME) is critical to the pathophysiology of cancer. These non-malignant host cells, consisting of a variety of stromal, immune and endothelial cells, engage in a complex bidirectional crosstalk with the malignant tumor cells. Mesenchymal stem/stromal cells (MSCs) are one of these host cells, and they play a critical role in directing the formation and function of the entire TME. These MSCs are epigenetically reprogrammed by cancer cells to assume a strongly pro-tumorigenic phenotype and are referred to as carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs). Studies over the last decade demonstrate that CA-MSCs not only directly interact with cancer cells to promote tumor growth and metastasis, but also orchestrate the formation of the TME. CA-MSCs can differentiate into virtually all stromal sub-lineages present in the TME, including pro-tumorigenic cancer associated fibroblasts (CAF), myofibroblasts, and adipocytes. CA-MSCs and the CAFs they produce, secrete much of the extracellular matrix in the TME. Furthermore, CA-MSC secreted factors promote angiogenesis, and recruit immunosuppressive myeloid cells effectively driving tumor immune exclusion. Thus CA-MSCs impact nearly every aspect of the TME. Despite their influence on cancer biology, as CA-MSCs represent a heterogenous population without a single definitive marker, significant confusion remains regarding the origin and proper identification CA-MSCs. This review will focus on the impact of CA-MSCs on cancer progression and metastasis and the ongoing work on CA-MSC identification, nomenclature and mechanism of action.
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Affiliation(s)
- Len Frisbie
- Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Ronald J Buckanovich
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
| | - Lan Coffman
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
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He J, Yao X, Mo P, Wang K, Yang ZL, Tian NN, Zhu XQ, Zhao J, Pang RQ, Ruan GP, Pan XH. Lack of tumorigenesis and protumorigenic activity of human umbilical cord mesenchymal stem cells in NOD SCID mice. BMC Cancer 2022; 22:307. [PMID: 35317758 PMCID: PMC8941803 DOI: 10.1186/s12885-022-09431-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 03/08/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The tumorigenesis of infused umbilical cord mesenchymal stem cells (UC-MSCs) is being preclinically evaluated. METHODS We observed tumor formation in NOD SCID mice after a single subcutaneous injection of hUC-MSCs and the effect of these cells on tumor growth in tumor-bearing mice. Three generations (P5, P7, and P10) of hUC-MSCs (1 × 107) from two donors (hUC-MSC1 and hUC-MSC2) were inoculated subcutaneously into NOD SCID mice. Subcutaneous transplantation models were established in NOD SCID mice with human cervical cancer HeLa cells (solid tumor) and human B cell lymphoma Raji cells (hematological tumor). Then, the animals were euthanized, gross dissection was performed, and tissues were collected. Various organs were observed microscopically to identify pathological changes and tumor metastasis. RESULTS In the tumorigenesis experiment, no general anatomical abnormalities were observed. In the tumor promotion experiment, some animals in the HeLa groups experienced tumor rupture, and one animal died in each of the low- and medium-dose hUC-MSC groups. The results may have occurred due to the longer feeding time, and the tumor may have caused spontaneous infection and death. Pathological examination revealed no metastasis to distant organs in any group. In the Raji tumor model, some animals in each group experienced tumor rupture, and one animal in the medium-dose hUC-MSC group died, perhaps due to increased tumor malignancy. Thus, hUC-MSCs neither promoted nor inhibited tumor growth. No cancer cell metastasis was observed in the heart, liver, spleen, lungs, kidneys or other important organs, except that pulmonary venule metastasis was observed in 1 animal in the model group. CONCLUSIONS Injected hUC-MSCs were not tumorigenic and did not significantly promote or inhibit solid or hematological tumor growth or metastasis in NOD SCID mice.
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Affiliation(s)
- Jie He
- Kunming Medical University, 920th Hospital Clinical College, Yunnan Province, Kunming, 650000, China
| | - Xiang Yao
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Ping Mo
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Kai Wang
- Kunming Medical University, 920th Hospital Clinical College, Yunnan Province, Kunming, 650000, China
| | - Zai-Ling Yang
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Ni-Ni Tian
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Xiang-Qing Zhu
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Jing Zhao
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Rong-Qing Pang
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Guang-Ping Ruan
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China.
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China.
| | - Xing-Hua Pan
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China.
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China.
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Analysis of the Interaction of Human Neuroblastoma Cell-Derived Cytochalasin B Induced Membrane Vesicles with Mesenchymal Stem Cells Using Imaging Flow Cytometry. BIONANOSCIENCE 2022; 12:293-301. [PMID: 35261871 PMCID: PMC8894839 DOI: 10.1007/s12668-021-00931-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 11/24/2022]
Abstract
At present, there is an increasing interest in the potential role of extracellular vesicles (EVs), acting as multi-signal messengers of the tumor stroma, in the development and progression of tumor. Tumor cell-derived EVs are considered a potential vector for the targeted delivery of antitumor agents due to the ability to fuse with parental cells through endocytosis and release their contents into the cytoplasm of the recipient cell. Tumor cell-derived EVs could be also used for priming immune cells and therapeutic vaccine development. It is also known that mesenchymal stem cells (MSCs) have a tropism toward tumor niches. It is believed that MSC migration to the tumor is due to its inflammatory signaling. Presumably, with the accumulation of MSCs at tumor sites, these cells differentiate into pericytes or tumor-associated fibroblasts, thereby forming a supporting tumor growth microenvironment. However, besides the ability to promote tumor progression, MSCs can also suppress its growth by inhibiting proliferation and cell cycle progression, and angiogenesis. Thus, the further studies of the MSC role in TME and MSC interaction with other cells of the tumor stroma, including through EVs, are of particular interest. To increase the yield of vesicles the isolation method based on pharmacological disorganization of the actin cytoskeleton induced by treating with cytochalasin B was used in this study. In this investigation the interaction of SH-SY5Y neuroblastoma cell-derived membrane vesicles, obtained using cytochalasin B (CIMVs), with human bone marrow-derived MSCs was analyzed using imaging flow cytometry. Using transmission electron microscopy, it was shown that CIMVs have a size similar to that of natural microvesicles, which is 100–1000 nm. Using imaging flow cytometry, it was shown that after 24 h of co-cultivation 6% of the MSCs contained a large number of CIMVs, and 42% of the MSCs contained a small amount of CIMVs. Cultivation of MSCs with SH-SY5Y cell-derived CIMVs also induced dose-dependent decrease in the expression of CD markers typical for MSCs. Thus, the internalization of SH-SY5Y cell-derived CIMVs within MSCs and the ability of the CIMVs to modulate immunophenotype of the recipient cells were shown. However, further studies are required to determine the effect of CIMVs on pro- or antioncogenic phenotype and function of MSCs.
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Szewc M, Radzikowska-Bűchner E, Wdowiak P, Kozak J, Kuszta P, Niezabitowska E, Matysiak J, Kubiński K, Masłyk M. MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents-A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives. Int J Mol Sci 2022; 23:2745. [PMID: 35269887 PMCID: PMC8911180 DOI: 10.3390/ijms23052745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.
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Affiliation(s)
- Monika Szewc
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Elżbieta Radzikowska-Bűchner
- Department of Plastic, Reconstructive and Maxillary Surgery, Central Clinical Hospital MSWiA, 02-507 Warsaw, Poland;
| | - Paulina Wdowiak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Piotr Kuszta
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Ewa Niezabitowska
- Department of Urology and Urological Oncology, Multidisciplinary Hospital in Lublin, 20-400 Lublin, Poland;
| | - Joanna Matysiak
- Department of Chemistry, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
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Eberspacher C, Mascagni D, Ferent IC, Coletta E, Palma R, Panetta C, Esposito A, Arcieri S, Pontone S. Mesenchymal Stem Cells for Cryptoglandular Anal Fistula: Current State of Art. Front Surg 2022; 9:815504. [PMID: 35252334 PMCID: PMC8889088 DOI: 10.3389/fsurg.2022.815504] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/24/2022] [Indexed: 11/19/2022] Open
Abstract
Anal fistula is a common disease that needs surgical treatment to be resolved. Despite a variety of surgical options, the major problem is still to cure complex fistulas without any recurrence in the long-term follow-up but, at the same time, to avoid an impairment of continence. In recent years, one solution has been the application of mesenchymal stem cells derived from adipose tissue, especially in association with other treatments, such as the use of fibrin glue or the previous application of a seton. Their initial use in fistulas associated with Crohn's disease has shown encouraging results. In this non-systematic review our aim is to analyze the use in cryptoglandular fistulas: the rate of healing is not so high, and the number of studies is limited. Therefore, further randomized controlled trials are needed to establish their efficacy in the case of complex cryptoglandular anal fistulas and their possible complications.
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45
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Safari F, Shafiee Nejad N, Aghaei Nejad A. The inhibition of Panc1 cancer cells invasion by hAMSCs secretome through suppression of tyrosine phosphorylation of SGK223 (at Y411 site), c-Src (at Y416, Y530 sites), AKT activity, and JAK1/Stat3 signaling. Med Oncol 2022; 39:28. [PMID: 35059869 DOI: 10.1007/s12032-022-01649-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/05/2022] [Indexed: 11/30/2022]
Abstract
SGK223 is a scaffolding protein involving in the oncogenic tyrosine kinase signaling. SGK223 was phosphorylated at Y411 by c-Src and in response to the Epidermal growth factor receptor (EGFR). Tyrosine phosphorylated SGK223 at Y411 enables to interact with CSK resulting up regulation of c-Src activity and promotion of the cell migration. Human amniotic mesenchymal stromal cells (hAMSCs) are a population of multipotent cells that it was considered to be as a potential platform in cancer therapy. Herein, we employed a co-culture system to clarify the effects of hAMSCs secretome through tyrosine phosphorylation of c-Src, SGK223, AKT activity, and JAK1/Stat3 signaling in Panc1 pancreatic cancer cells. By using the 0.4 μm pore sized transwell membranes, both cell lines were firstly co-cultured for 72 h. Next, c-Src activity (tyrosine phosphorylation levels at Y530 and Y416), tyrosine phosphorylation level of SGK223 (at Y411), AKT activity, and JAK1/Stat3 signaling in Panc1 cells after treatment with hAMSCs were evaluated. Our results showed that hAMSCs have the inhibitory effects on Panc1 pancreatic cancer cells invasion and it suggests that the suppression of c-Src activity, SGK223 expression, AKT activity, and JAK1/Stat3 signaling may be as critical targets in pancreatic cancer therapy.
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Affiliation(s)
- Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
| | - Nasim Shafiee Nejad
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Azadeh Aghaei Nejad
- Department of Biology, University Campus 2, University of Guilan, Rasht, Iran
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46
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He W, Li Q, Lu Y, Ju D, Gu Y, Zhao K, Dong C. Cancer treatment evolution from traditional methods to stem cells and gene therapy. Curr Gene Ther 2021; 22:368-385. [PMID: 34802404 DOI: 10.2174/1566523221666211119110755] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/25/2021] [Accepted: 09/16/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Cancer, a malignant tumor, is caused by the failure of the mechanism that controls cell growth and proliferation. Late clinical symptoms often manifest as lumps, pain, ulcers, and bleeding. Systemic symptoms include weight loss, fatigue, and loss of appetite. It is a major disease that threatens human life and health. How to treat cancer is a long-standing problem that needs to be overcome in the history of medicine. METHOD Traditional tumor treatment methods are poorly targeted, and the side effects of treatment seriously damage the physical and mental health of patients. In recent years, with the advancement of medical science and technology, the research on gene combined with mesenchymal stem cells to treat tumors has been intensified. Mesenchymal stem cells carry genes to target cancer cells, which can achieve better therapeutic effects. DISCUSSION In the text, we systematically review the cancer treatment evolution from traditional methods to novel approaches that include immunotherapy, nanotherapy, stem cell theapy, and gene therapy. We provide the latest review of the application status, clinical trials and development prospects of mesenchymal stem cells and gene therapy for cancer, as well as their integration in cancer treatment. Mesenchymal stem cells are effective carriers carrying genes and provide new clinical ideas for tumor treatment. CONCLUSION This review focuses on the current status, application prospects and challenges of mesenchymal stem cell combined gene therapy for cancer, and provides new ideas for clinical research.
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Affiliation(s)
- Wenhua He
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Qingxuan Li
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Yan Lu
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Dingyue Ju
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Yu Gu
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Kai Zhao
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
| | - Chuanming Dong
- Department of Anatomy, Medical College of Nantong University, Nantong 226001. China
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Ghollasi M, Ghasembaglou S, Rahban D, Korani M, Motallebnezhad M, Asadi M, Zarredar H, Salimi A. Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight. Int J Stem Cells 2021; 14:351-365. [PMID: 34456189 PMCID: PMC8611310 DOI: 10.15283/ijsc20146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 06/01/2021] [Accepted: 06/16/2021] [Indexed: 11/10/2022] Open
Abstract
The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.
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Affiliation(s)
- Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shahram Ghasembaglou
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Korani
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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de Miranda MC, Ferreira ADF, de Melo MIA, Kunrath-Lima M, Goes AMD, Rodrigues MA, Gomes DA, Faria JAQA. Adipose-derived stem/stromal cell secretome modulates breast cancer cell proliferation and differentiation state towards aggressiveness. Biochimie 2021; 191:69-77. [PMID: 34454978 DOI: 10.1016/j.biochi.2021.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/29/2021] [Accepted: 08/24/2021] [Indexed: 11/18/2022]
Abstract
It is becoming increasingly evident that mesenchymal stem/stromal cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor proliferation, angiogenesis, invasion, and metastasis, as well as mediate therapeutic resistance. Consequently, understanding the regulatory mechanisms of ASCs that influence the tumor microenvironment may provide an avenue for further treatment. To understand the role of the ASC secretome in breast cancer cell proliferation, death, and phenotype alteration, adipose-derived stem cell-conditioned medium (mASC) was used to cultivate MCF-7 and MDA-MB-231 cells. These breast cancer cells in mASC showed a shorter doubling time, higher frequency of EdU positivity, and higher levels of phosphorylated histone 3. In addition, increased expression of cyclin B1 was observed, suggesting that proliferation was induced. The mASC was also able to increase apoptosis in MCF-7 cells, which was confirmed by caspase-7 activation. The number of tumor-initiating cells (CD44+ CD24-/low) and migration capacity were increased in cells cultivated in mASC. These data collectively suggest that ASC-conditioned medium can induce selective pressure by increasing cell proliferation, giving rise to a more aggressive phenotype in MCF-7 and MDA-MB-231 cells. Our study provides a foundation for further elucidation of the precise mechanism underlying ASCs in breast cancer cells and the modulation of ASCs in potential therapeutic uses.
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Affiliation(s)
- Marcelo Coutinho de Miranda
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Andrea da Fonseca Ferreira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Mariane Izabella Abreu de Melo
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marianna Kunrath-Lima
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Alfredo Miranda de Goes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Michele Angela Rodrigues
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Dawidson Assis Gomes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment. Cells 2021; 10:cells10092201. [PMID: 34571851 PMCID: PMC8468635 DOI: 10.3390/cells10092201] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/23/2021] [Accepted: 08/23/2021] [Indexed: 01/23/2023] Open
Abstract
Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.
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50
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Zhang Q, Yang X, Liu H. Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment. Technol Cancer Res Treat 2021; 20:15330338211037821. [PMID: 34427131 PMCID: PMC8388228 DOI: 10.1177/15330338211037821] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.
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Affiliation(s)
- Qian Zhang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiangling Yang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huanliang Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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